Azecino(2,1-a)tetrahydroisoquinolines and process for their production

ABSTRACT

THE PRESENT INVENTION RELATES TO COMPOUNDS OF THE FORMULA:   1,2-(-CH(-R3)-A-CH(-R4)-CH2-(CH2)N-CH2-C(=B)-),6-R1,7-R2-   1,2,3,4-TETRAHYDROISOQUINOLINE,   1,2-(=C(-R3)-R5-CH(-R4)-CH2-(CH2)N-CH2-C(=B)-),2-R6,6-R1,   7-R2-1,2,3,4-TETRAHYDROISOQUINOLINE,   (2-R6,6-R1,7-R2-1,2,3,4-TETRAHYDROISOQUINOL-1-YL)-CH(-R3)-   CH&lt;(-CH(-R4)-CH2-(CH2)N-CH2-COO-) AND   6-R1,7-R2-1,2,3,4-TETRAHYDROISOQUINOLINE   WHEREIN B IS OXYGEN OR HYDROGEN; A IS &gt;CHOH, &gt;CHOSO2C6H4CH3, &gt;C=O, &gt;CH2, &gt;C=NOH, &gt;C=NOCOCH3, &gt;CONH; R1 AND R2 ARE HYDROGEN, LOWER ALKOXY, HYDROXY, OR IF TAKEN TOGETHER, METHYLENEDIOXY; R3 IS HYDROGEN, HALOGEN, LOWER ALKYL, ARALKYL, LOWER ALKOXY; R4 IS ALKYL, ARALKYL, ARYL, CARBOALKOXY, HALOGEN; N IS 1-20; R5 IS &gt;C=O OR &gt;C=NOH; R6 IS HYDROGEN, ACYL OR TOSYL; R7 IS HYDROXY, LOWER ALKOXY, AMINE, LOWER ALKYLAMINE AND ARALKYLAMINE. THESE COMPOUNDS ARE USEFUL AS ANTIHYPERTENSION AGENTS.

r 3,555,029 Ice Patented Jan. 12, 197

United States Patent Plains, N.J., a corporation of Delaware (V) N0 Drawing. Filed July 31, 1967, Ser. No. 657,086 Int. Cl. C07d 39/00 US. Cl. 260-286 Claims 10 ABSTRACT OF THE DISCLOSURE The present invention relates to compounds of the formula: v (VI) (V) v I (VI) wherein B is oxygen or hydrogen; A is CHOH, wherein B is oxygen or hydrogen; A is CHOH, CH0SO C H CH C O, CH C=NOH, C=NOCOCH CONH; R and R are hydrogen, CHOSO2C6H4CH3 lower alkoxy, hydroxy, or if taken together, methylene- 2, 3, dioxy; R is hydrlgglen, halogen, lolwer agkylfiiaralkyl ll, llower C0NH r a ox a0 en; & g i g is i sfi f R6 isyhydrogen R and R are hydrogen, lower alkoxy, hydroxy, or if acyl or tosyl; R7 is hydroxy lower alkoxy, amine lower taken together, methylenedioxyg R is hydrogen, halogen, alkylamine and aralkylamine. These compounds are uselower alkyl aralkyl lower PF R4 i aralkyl ful as antihypertension agents 7 aryl, car boalkoxy, halogen; n is 1-20; R is C=O or k y @NOH; R is hydrogen, acyl or tosyl; R 18 hydroxy, lower alkoxy, amine, lower alkylamine and aralkylamine. In the above definitions for R R R and R lower The present invention relates to certain isoquinoline alkyl h h 1ower 1k 1 portion f 1 lk i meant derivatives and more particularly this invention relates to include from 1 to 6 carbon atoms such as methyl, to azecino['2,1-a]tet y q hav g t e f ethyl, propyl, isopropyl, butyl, isobutyl and the like; aryl mula: p s is meant to include both monohomocyclic systems such as phenyl and mono-, heterocyclic systems such as pyridyl, furyl, and the like; halogen is meant to include all four N B members of its family that is fluorine, bromine, iodine,

and chlorine. Acyl is a residue of a carboxylic acid pref- 1 2) erably that of a lower alkanoyl acid, for example, acetyl,

R A propionyl and the like, or benzoyl.

it The present invention also embraces within its scope,

(111) pharmaceutical dosage forms containing the above com:

pounds as their active ingredients, as well as novel processes for the production of the above compounds.

The compounds of this invention have a pharmacological profile similar to guanethidine exhibiting guani ethidine-like activity in a mammalian body and are ,accordingly useful in the treatment of hypertension. Generally speaking, they are used in a similar manner as guanethidine. In order to use these compounds as a'nti- (IV) hypertension agents, they are combined with an inert pharmaceutical carrier such as lactose, mannitol, dicalciurn phosphate, or other standard diluents and excipients to form dosage forms such as tablets, dispersible powders, and the like. They may also be combined with a liquid vehicle such as isotonic saline, sterile water, and the like, to form dosage forms suitable for parenteral administration. Generally, a daily dose of about 25 to 100 mg. is recommended to produce the desired antihypertensive effects. Additionally, the compounds of this invention exhibit inotropic activity in the mammalian cardiovascular system and therefore they are also useful as agents in relieving arrythmias and angina pectoris.

According to the process of this invention, the above compounds of type III where A is @O and B is (CH2)n 3 4 may be prepared by reacting Compound I and Compound II RSCHQ R2 Generally, the reaction can be effected at the temperature of from about 80 to 100 C. in a lower molecular weight alcohol, for example, ethanol or water. This reaction is described in detail in Examples 1-5. Starting materials I may be prepared according to procedures cited by R. C. 'Elderfield in Heterocyclic Compounds, vol. 4, p. 349, published by I. Wiley & Sons of New York (1952). Start ing materials II can be obtained by methods cited by H. Henceka in Chemie der Beta-Dicarbonyl-Verbindungen p. 29, Springer Verlag Berlin, 1950.

Compound III obtained by above described procedure is then subjected to well-known chemical reactions. These are, oxime formation described in Example 6; reductions with complex metal hydrides, described in Examples 7-11; acylation or tosylation described in Examples 12-14; and Beckmann rearrangement described in Example 15.

Those compounds having structure III wherein A is C=O or %NOH give in the presence of a base or an acid compound of type IV wherein R is C=O or C=NOH, and R is H, acyl, or p-toluenesulfonyl group. These compounds are described in Examples 16 to 18. Compound V may be obtained from Compounds III which have B=O and A= CHOH by reacting Compounds III with reagents, such as HCl, p-toluenesulfonyl chloride, and the like under anhydrous conditions. This reaction is described in detail in Example 19. Finally, compounds VI are obtained by carrying out the latter reaction in water, lower aliphatic alcohol or amine whereby the lactone ring is cleaved as described in Example 20.

The basic compounds of this invention form pharmaceutically acceptable acid addition salts With mineral acids, such as hydrochloric acid, hydrobromic acid, hydriodic acid, nitric acid, phosphoric acid, and sulfuric acid; and organic acids such as acetic acid, citric acid, tartaric acid, lactic acid, benzenesulfonic acid, toluene sulfonic acid, etc., and these acid addition salts are also included within the scope of this invention.

The following examples are included in order further to illustrate the invention. Temperatures are given in degrees centigrade.

4 EXAMPLE 1 CH O A mixture of 12.3 g. of 6,7-dimethoxy-3,4-dihydroisoquinoline and 10 g. of 2-acetyl-Z-methylcyclohexanone in 250 ml. of water, is refluxed with stirring for 16 hours. The aqueous portion is decanted from the cooled reaction mixture and the remaining gum is boiled in 70 ml. of acetonitrile and chilled. Filtration and drying of the solid alfords 6.5 g. (30%) of 5,6,l0,11,12,13,15,15a-octahydro- 2,3-di-methoxy-l3-methyl 9H azecino [2,1-a]isoquinolin- 8,14-dione. Recrystallization from acetonitrile yields analytical material. M.P. 240-244; A m (6) 285 (18,400); x 1520 (s.), 1620 (v.s.), 1700 (s.) cmr Analysis.Calcd. for C20H27NO4 (percent): C, 69.54; H, 7.88; N, 4.05. Found (percent): C, 69.52; H, 7.96; N, 4.24.

EXAMPLE 2 5,6,10,11,12,13,15,15a-octahydro-3-methoxy-13-methyl- 9H-azecino[2,1-a]isoquinolin-8,14-dione A solution of 6-methoxy-3,4-dihydroisoquinoline (2 g.) and 2-acetyl-2-methylcyclohexanone (2 g.) in 50 ml. of water is refluxed for 15 hours. An additional 1 g. of 2- acetyl-2-methylcyclohexanone is added and refluxing is continued for a total of 22 hours. The cooled reaction mixture is extracted with ml. of ether. The ethereal solution is washed with dilute hydrochloric acid, dried, concentrated to about 25 ml., and chilled to obtain crystalline 5,6,10,11,12,l3,15,15a-octahydro 3 methoxy 13- methyl-9H-azecino[2,l-a]isoquinolin 8,14 dione. The crystalline product (0.55 g., 14%) is crystallized from ethyl acetate. M.P. 189-191; R, 0.7; A 1706 (s.), 1615 (v.s.) cmf Analysis.Calcd. for C H NO (percent): C, 72.35; H, 7.99; N, 4.44. Found (percent): C, 72.44; H, 8.01; N, 4.53.

EXAMPLE 3 5,6,l0,11,12,13,15,l5a-octahydro-13-methyl-9H- azecino[2,1-a]isoquinolin-8,14-dione A solution of 3,4-dihydroisoquinoline (2.62 g.) and 2- acetyl-2-methylcyclohexanone (3.08 g.) in ml. of

water is refluxed for 22 hours and allowed to cool. The reaction mixture is extracted with 70 ml. of chloroform. The extract is washed with dilute hydrochloric acid, dried and concentratedunder reduced pressure to obtain 5,6,10, 11,12,13,15, 15a octahydro-13-methyl-9H-azecin0[2,l-a] isoquinolin-8,14-dione as a residue. The residue is crystallized from isopropanol twice. Yield: 0.1 g. (1.7%); M.P. 151153; A 1730 (s.), 1630 (v.s.) cmr- Analysis.-Calcd. for C H NO (percent): C, 75.75; H, 8.12; N, 4.91. Found (percent): C, 75.60; H, 8.03; N, 4.80.

EXAMPLE 4 5,6,9,10,l1,12,13,14,15,15a-decahydro-2,3,IS-trimethoxy- 13-methyl-9H-azecino [2, l-a] isoquinolin-8, l4-dione A solution of 5,6-dimethoxy-3,4-dihydroisoquinoline (5.2 g.) and 5 g. of 2-methoxyacetyl-2-methyl-cyclohexanone in 125 ml. of water is refluxed for 19 hours. The cooled reaction mixture is acidified with concentrated hydrochloric acid and extracted with chloroform yielding 7.7 g. of non-basic material which is chromatographed on 400 g. of Florisil with ethyl acetate elution to yield: 1.2 g. of 5,6,9,10,11,12,13,14,15,15a-decahydro-2,3,15- trimethoxy 13 methyl 9H azecino [2,1-a]isoquinolin- 8,14-dione (12%); Rf 0.5. Crystallization from ethylacetate afiords an analytical sample. M.P. 161.5-163; k 1705 (m.), 1635 (s.), 1105, (s.) cmr Analysis.Calcd. for C H NO (percent): C, 67.18; H, 7.79; N, 3.73. Found (percent): C, 67.09; H, 7.68; N, 4.00,

EXAMPLE 5 5,6,9,10,11,12,13,14,15,16,17,18,19,20=,21,21ahexadecahydro-2,3 dimethoxy 19' methyl 8H azacyclohexadeca [2,l-a]isoquinolin-8,20-dione (14) A solution of 6.7-dimethoxy-3,4-dihydroisoquinoline (2.85 g.) and 3.6 g. of 2-acetyl-Z-methylcyclododecanone in 60 ml. of water is refluxed for 34 hours. The aqueous phase is decanted from the cooled reaction mixture and the solid is dissolved in benzene and Washed with dilute hydrochloric acid and Water. The solvent is distilled off and the residue is triturated with Skellysolve C; to yield 1.5 g. of 5,6,9,10,11,12,13,l4,l5,16,l7,18,l9,20,21,21ahexadecahydro 2,3 dimethoxy 19 methyl 8H- azacyclohexadeca[2,l-a]isoquinolin 8,20 dione (14). Crystallization from ethanol affords analytical material. M.P. 129-130; A (e) 284 (4,200); A 1695 (s.), 1630 (v.) cm.-

Analysis.Calcd. for C H NO (percent): C, 72.69; H, 9.15; N, 3.26. Found (percent): C, 72.88; H, 9.10; N, 3.18.

EXAMPLE 6 HON 5 ,6,l0,1 1,12,13,15,15a-octahydro-2,3-dimethoxy-l3-methyl-9H-azecino [2, l-a] isoquinoline-8, 1'4-dione l4-oxime A solution of 10 g. of 5,6,10,11,12,13,15,l5a-octahydro-2,3-dimethoxy-13-methyl-9H-azecino [2, l-a] isoquinoline-8,14-dione in 750 ml. of ethanol is combined with a solution of 25 g. of NH OH-HCl in 150 ml. of H 0, treated with ml. of 10% NaOH and is refluxed for 15 hours. After evaporation of the ethanol in vacuo, the residue is treated with 500 ml. of H 0, made acidic with conc. HCl, and extracted 3 times with 300 ml. portions of chloroform. The chloroform solution is dried and concentrated to dryness in vacuo. Crystallization of the crude oxime from methanol affords 9.1 g. (87%) of 5,6,10,11,12,13,15,15a octahydro 2,3 dimethoxy 13- methyl 9H azecino[2,1-a]isoquinoline 8,14-dione 14-oxime. Recrystallization from methanol gives the analytical material M.P. 217-220; A m (6) 282 (4500), 286 (4500); A 3200 (m.), 1615 (s.), 1590 (s.), 1520 (m.s.) cmr Analysis.Calcd. for C H N O (percent): C, 66.64; H, 7.83; N, 7.77. Found (percent): C, 66.60; H, 7.80; N, 7.51.

EXAMPLE 7 CH CH O N 5,6,9,10,11,12,13,14,15,15a-decahydro-14-hydroxy-2,3-dimethoxy-13-methyl-9H-azecino [2,1-a] isoquinolin-S-one A solution of 17.2 g. of 5,6,10,l1,12,13,15,15a-0ctahydro 2,3 dimethoxy 13 methyl 9H azecino[2,1-a] isoquinoline-8,14-dione in 400 ml. of CHCl and 400 ml. of CH OH is treated, portion-wise, with 9 g. KBH and stirred overnight. The solvent is removed in vacuo and the residue is dissolved in 250 ml. of chloroform and 100 ml. of water. The chloroform layer is separated, dried over Na SO and evaporated, to yield 16.3 g. (94%) of 5,6,9,10,11,12,l3,l4,15,15a decahydro 14 hydroxy- 2,3 dimethoxy 13 methyl 9H azecino[2,l-a]isoquinolin-8-one. A two-fold recrystallization from ethylacetate affords analytical material; M.P. 163-194; A 284; A 1515 (s.), 1605 (s.), 3350 (v.w.), 3500 (w.) cm.-

Analysis.-Calcd. for C H NO (percent): C, 69.14; H, 8.41; N, 4.03. Found (percent): C, 68.92; H, 8.54; N, 4.03.

EXAMPLE 8 8H-azccino[2,l-a]isoquinolin-8-one in 500 ml. of tetrahydrofuran is treated with 8 g. of LiAlH refluxed for 8 hours, and allowed to stand overnight. Excess LiAlH is destroyed with H O, the solids are filtered oif and washed with tetrahydrofuran. Combined filtrate and washings are concentrated to dryness under reduced pressure. The residue is dissolved in ethyl acetate and extracted with 3 N HCl. The acid solution is made basic with NaOH and extracted with chloroform. Evaporation of the chloroform solution gives 6.32 g. (80%) of crude isomeric mixture.

Chromatography of a portion of crude product on Florisil (40 g./g.) with ethyl acetate affords isomer A (R, 0.7) which is dissolved in dilute HCl and treated with an excess of 17% perchloric acid. The precipitated perchloric acid salt is recrystallized from isopropanol. M.P. 160.

Analysis.-Calcd. for C H NO -HClO (percent): C, 55.36; H, 7.43; N, 3.23; CI, 8.17. Found (percent): C, 55.62; H, 7.33; N, 3.47; 01, 8.39.

)t 3400 (m.), 3100 (w.), 1610 (w.), and 1525 (m.) cm" Chromatography of a portion of crude product on silica gel (100 g./ g.) with ethyl acetate affords chromatographically pure isomer B as gum (R =0.85). The hydrochloride salt, prepared by dissolving the gum in ethyl acetate and treating with ethereal hydrogen chloride, is crystallized from isopropanol three times to give the analytical sample. M.P. 183-185 A 3300 (s.), 2550 (m.), 1610 (w.), 1520 (s.) cm

AnaIysis.Ca.lcd. for C H NO -HCl (percent): C, 64.94; H, 8.72; N, 3.79; Cl, 9.58. Found (percent): C, 65.06; H, 8.88; N, 4.09; Cl, 9.35.

EXAMPLE 9 5,6,9,10,l1,12,13,14,15,15a-decahydro-2,3-dimetl1oxy- 13-methyl-8H-azecino[2,1-a]isoquinoline perchlorate A solution of 3 g. of 5,6,9,10,l1,12,13,14,15,15a-decahydro-14-hydroxy-2,3-dimethoxy-13-methyl 8H azecino[2,1-a1isoquinoline-8-one p-toluenesulfonate in 250 ml. of tetrahydrofuran is treated with 3 g. of LiAlH, and refluxed for 4 hours. Excess LiAlH is destroyed by addition of H 0. The solids are filtered oh and washed with hot tetrahydrofuran. Combined filtrate and washings are concentrated under reduced pressure. The oily residue is dissolved in ether and extracted with 2 N HCl. The acid solution is made basic with 10% NaOH and extracted with CHCl Drying and evaporation of the CHCl solution yields the crude product. Chromatography on g. of Florisil with ethyl acetate as the eluant aflords chromatographically pure material (Rf 0.9) which is dissolved in 10 ml. of methanol and treated with 2 ml. of 70% perchloric acid. After evaporation of the methanol the residue is triturated with cold water and crystallized from isopropanol to yield 1.42 g. (51%) of 5,6,9,10,11,12,13,14, 15,15a-decahydro 2,3 dimethoxy-l3-methyl-8H-azecino[2,1-a]isoquinoline perchlorate. M.P. 161-163". Recrystallization from isopropanol affords analytical material M.P. 162l65. (Dried at 140/O.1 mm. 5 hr.).

AnaIysis.-Calcd. for C H NO -HCl (percent): C, 57.48; H, 7.72; N, 3.35; Cl, 8.48. Found (percent): C, 57.24; H, 7.88; N, 3.61; Cl, 8.60.

EXAMPLE 10 HON A solution of 10 g. of 5,6,10,11,12,13,15,15a-octahydro-2,3-dimethoxy-13-methyl 9H azecino[2,l-a]isoquinoline-8,14-dione 14-oxime in one 1. of tetrahydrofuran is allowed to cool, treated with 5 g. of LiAlH and stirred at room temperature for 3.5 hours. Excess LiAlH is destroyed with Water, the inorganic material is filtered oil and Washed with hot tetrahydrofuran. Combined and dried filtrate and washings are evaporated to dryness. The oily residue (10 g.) is dissolved in ethyl acetate, and adsorbed on a 250 g. Florisil column. Elution with ethyl acetate followed by chloroform yields 7.7 of 5,6,9,10,11,12,13,14,15,15a-decahydro 2,3 dimethoxy- 13-methyl-8H-azecino[2,1-a]isoquinoline 14 one oxime. The analytical sample is prepared by dissolving in hot Skelly B and allowing the solution to cool. M.P. 65- 6 p.p.m. d. 1.05 (CH -CH), 3.84 (CH O), multiplet in 3.84.2 area (H-15a, equatorial H-6), 6.60, 7.07 (aromatic H); A m (e) 281 (4160); k 3200 (m.), 1605 (W.), 1510 (s.) cm.

Analysis.Calcd. for C H N O (percent): C, 69.33; H, 8.73; N, 8.09. Found (percent): C, 69.25; H, 8.65; N, 8.19.

EXAMPLE 11 CiluO i CH O 2/ \/\l AN/ O H (13H:

5,6,8,9,10,11,12,13,14,15,16,16a-dedecahydro 2,3 dimethyl-13-methylisoquino[2,l-a] [1,5 ]diazacycloundec. in-15 one A solution of 3.68 g. of 5,6,9,l0,l1,12,13,14,l6,16a-decahydro-2,3-dimethoxy 13 methylisoquino[2,1-a][1,5] diazacycloundecine-8,15-dione in 400 ml. of tetrahydrofuran is chilled, treated with 3.6 g. of LiAlH and stirred at room temperature for 3 hours. Excess LiAlHd, is destroyed with Water with external cooling. The reaction mixture is filtered, and the cake is washed several times with tetrahydrofuran. The combined filtrate and washings are dried and evaporated under reduced pressure. The residue is crystallized from aqueous ethanol to yield 2.5 g. (71%) of analytically pure 5,6,8,9,10,11,12,13,14,15,16, 16a-dodecahydro 2,3 dimethoxy-l3-methylisoquino [2,1-a][1,5]diayacycloundecin-15-one. M.P. 173175; A m (6) 282 (4400); 286 (4400); A 3300 (m.), 1630 (s.), 1540 (m.), 1515 (m.s.) cmf AnaIysis.Calcd. for C H N O (percent): C, 69.33; H, 8.73; N, 8.09. Found (percent): C, 69.12; H, 9.03; N, 7.99.

EXAMPLE 12 CH30 i i 5,6,9,10,l1,12,13,14,15,15a decahydro-14-hydroxy-2,3- dimethoxy-l3-methyl-8H-azecino[2,l a]isoquinoline- 8-one-p-toluenesulfonate A solution of 1 g. of 5,6,9,10,11,12,13,l4,15,15a-decahydro 14 hydroxy 2,3 dimethoxy 13 methyl-9H- azecino[2,1-a]isoquinoline-8-one in 250 ml. of pyridine is treated dropwise (45 min.) with a solution of 11.4 g. of p-toluenesulfo'nyl chloride in 100 ml. ofpyridine, and is stirred at room temperature for 22 hours. The reaction mixture is concentrated under reduced pressure at a temperature not to exceed 40. The residue is dissolved in 250 ml. of chloroform, washed consecutively with dilute HCl, sodium hydroxide solution and H 0. Drying and evaporation of the chloroform solution yields 13.2 g. of 5,6,9,1 0,11,12,13,14,15a decahydro 14 hydroxy-2,3- dimethoxy-13-methyl 8H azecino[2,1-a]isoquinoline-8- one p-toluenesulfonate. Crystallization from 100 ml. is& propanol affords 3 g. (21%) of the product. Crystallization from ethyl acetate yields analytical material, M.P. 165-166", R; 0.5; k 1635'(s.), 1520 (m.), 915(v.s.) cm.- 1

Analysis.-Calcd. for C H NO S (percent): C, 64.65; H, 7.03; N, 2.79. Found (percent): C, 64.70; H, 7.15; N,*3.06.

EXAMPLE 13 5,6,9,10,1l,12,13,14,15,15a -decahydro 14-hydroxy-2,3- dimethoxy 13 methyl-8H-azecino 2,1-a] isoquinoline- 8-one benzoate A cooled solution of 0.3 g. 5,6,9,l0,11,12,13,14,15,15adecahydro 14 hydroxy 2,3 dimethoxy 13 methyl- 8H-azecino[2,1-a]isoquinolin-8-one in 25 ml. of pyridine is treated dropwise with asolution of 2 ml. of benzoyl chloride in 51 ml. of pyridine. After standing for 4 days at. room temperature the reaction mixture is concentrated in vacuo and the residue is dissolved in 50 ml. of chloroform and washed consecutively with water, in HCl and water. The chloroform solution is dried (Na SOQ and evaporated. The residue is taken up in ethyl acetate and passed through a short Florisil column. Evaporation of eluate yields 0.34 g. (85%) of crude 5,6,9,10,1l,12,l3, 14,15,15a decahydro 14 hydroxy 2,3-dimethoxy-13- methyl-SH-azecinb [2,1 a]isoquinolin-8-one Benzoate in the form of an oil. Crystallization from ethyl acetate affords analytical material M.P. 182184 C.; x cmr 1715 (s.), 1620.(s.).

Analysis.Calcd. for C H HO (percent): C, 71.81; H, 7.37; N, 3.10. Found (percent): C, 71.73; H, 7.57; N, 3.40. w

l 0 EXAMPLE 14 CHaO- C aO CHaCOON JHa 5,6,8,9,10,11,12,13,14,15a decahydro-2,3-dimethoxy-l3- methyl-l4H-azecino [2, l-a] isoquinolin-14-orre O-acetyl oxime A solution of 2 g. of 5,6,9,l0,l1,12,13,14,15,15a-decahydro 2,3 dimethoxy 13 methyl-8H-azecino[2,l-a] isoquinoline-14-one oxime in 50 ml. of pyridine is treated with 5 ml. of acetic anhydride and allowed to stand at room temperature overnight. The reaction is concentrated on a rotary evaporator below 60. The solution of the residue in 50 ml. of ethyl acetate is washed with 5% NaOH then with water and is evaporated under reduced pressure. Trituration of the residue with petroleum ether yields 1.86 (83%) of crude 5,6,8,9,10,11,12,- 13,14,15a decahydro 2,3 dimethoxy 13-methyl-14H- azecino[2,1-a]isoquinolin-l4-one O-acetyl oxime. A twofold crystallization from anhydrous ether affords analytical material M.P. 131-133"; A 1750 cmr 5 p.p.m. d. 1.12 (CH CH), 2.23 CHgCO), 3.85 (CH O), multiplet in 3.8-4.2 area (H-15a, equatorial H-6), 6.58, 6.58 (aromatic H).

Analysis.Calcd. for C H N O (percent): C, 68.01; H, 8.30; N, 7.27. Found (percent): C, 68.07; H, 8.39; N, 7.51.

EXAMPLE 15 3 O CH I 5,6,9,l0,1l,12,l3,l4,l6,16a decahydro 2,3-dimethoxy- 13 methylisoquino[2,1 a][1,5]diazacycloundecine- 8,15-dione Powdered 5,6,10,11,12,13,15,15a octahydro 2,3- dimethoxy 13 methyl 9H azecino[2,1-a]isoquinolin- 8,14 dione 14 oxime (5 g.) is added to polyphosphoric acid (100 g.) and heated on a steam bath (-100) stirring occasionally for 0.5 hr. After cooling, and dilution with one 1. of ice water with vigorous stirring, the mixture is extracted with CHCl Evaporation of combined and dried extracts yields the crude 5,6,9,10,11,12, 13,14,16,16a decahydro 2,3 dimethoxy 13 methylisoquino [2, l-a] [1,5]diazacycloundecine-8,15-dione which is crystallized from ml. of ethyl acetate to yield 4.05 g. (81%) of chromatographically pure material. Recrystallization from acetonitrile gives analytical material. M.P. 252-255; A my. (6) 282 (4550), 286 (4590); k 3450 (w.), 3350 (m.s.), 3300 (w.), 1160 (s.), 1630 (s.), 1545 (s.), 1515 (s.) cmf Analysis.Calcd. for C H N O (percent): C, 66.64; H, 7.83; N, 7.77. Found (percent): C, 66.73; H, 7.69; N, 7.63.

EXAMPLE 16 CH3 I O CH O 1,2,5,6,7,8hexahydro-l4,15-dimethoxy-9-methyl-3- benzazacyclotetradecine-4,10(3H,9H)-dione A solution of 5 g. of 5,6,10,11,12,13,15,15a-octahydro- 2,3 dimethoxy 1 3 methyl 9H azecino[2,1-a]

isoquinoline-8,14-dione in 125 ml. ethanol is treated with 6.5 ml. of a 0.17 N solution of sodium in ethanol, and refluxed for 1.5 hr. with exclusion of moisture. The solvent is removed in vacuo and the residue is dissolved in 125 ml. of CHCl and washed twice with H O. Drying and concentration of the solution yields crude 1,2,5,6,7,8- hexahydro 14,15 dimethoxy 9 methyl 3 benzazacyclotetradecine 4,10(3H,9H) dione. Crystallization from 95% ethanol and recrystallization from ethyl acetate affords 0.56 g. (11.2%) of analytical material. M.P. 188190; A (5) plateau 222 (11,700), 246 (11,200), shoulder 305 (11,700), 339 (16,000); A 3330 (m.), 1660 (s.), 1640 (s.), 1600 (s.) 1535 (m.), 1525 (s.) cm.

Analysis.-Calcd. for C H NO (percent): C, 69.54; H, 7.88; N, 4.06. Found (percent): C, 69.77; H, 8.02; N, 4.13.

EXAMPLE 17 CHaO- NH 1 l HON CH3 1,2,3,4,5 ,6,7,8-octahydro-14, 15 -dimethoxy-9-methyl-3- benzazacyclotetradecin-10(9H) -one oxime The solution of 5,6,9,10,11,12,13,14,15,14a decahydro- 2,3 dimethoxy 13 methyl 8H azecino[2,1-a]iso quinoline-14-one oxime (3,6 g.) in 50 cc. of 3 N HCl is stirred at room temperature for 1 hour. The acidic suspension is made basic with 10% NaOH and extracted with CHCl The dried chloroform solution is evaporated in vacuo. The residue is crystallized from 50 ml. of ethyl acetate to yield 1.0 g. (28%) of 1,2,3,4,5,6,7,8- octahydro 14,15 dimethoxy 9 methyl 3 benzazacyclotetradecin 10(9H) one oxime. Evaporation of the ethyl acetate mother liquor and treatment of the residue with 20 cc. of 6 N HCl for 2 hours at room temperature afforded an additional 0.9 g. (25%) of 1,2,3,4,5,6,7,8-octahydro 14,15 dimethoxy 9 methyl- 3 benzazacyclotetradecin 10(9H) one oxime. An analytical sample is prepared by a single crystallization from methanol. M.P. 199-202 (dec.); 6 p.p.m. d. 1.15 (CH CH), 382 (CH O), 6.88, 7.20, 7.29 (ca. 1:122, H-ll, H-12, H-13, H-16); 8 m (e) 221 (13,500), 238 (12,400), 295 (15,800), 325 (16,800); x 3300 (m.), 2650 (m.), 1600 (m.), 1510 (s.) cm.-

Analysis.Calcd. for C H N O (percent): C, 69.33; H, 8.73; N, 8.09. Found (percent): C, 69.28; H, 8.85; N, 8.32.

EXAMPLE 18 II omoooN CHQO due which is triturated with cold H 0 and dissolved in chloroform. The solution is washed with water, dried and concentrated in vacuo to yield 1.16 g. (52%) of 3-acetyl- 1,2,3,4,5,6,7,8 octahydro 14,15 dimethoxy 9 methyl- 3 benzazacyclotetradecin 10(9H) one O-acetyl oxime. Two fold crystallization from ethyl acetate gives analytical material. M.P. 5962; A (e) shoulder 224 (14,500) 242 (14,900), plateau 303 (13,800), 336 (17,700); A cm.- 1750 (s.), 1635 (s.); 6 p.p.m. d. 1.32 (CH CH), 2.12 (CH 'CON), 2.23 (CHgCOO), 3.93 (CH O), 6.75, 6.87, 7.15, 7.38 (four protons, AB quartet superimposed on two singlets, H-ll, H-12, H-13, H-16).

Analysis.Calcd. for C H N O (percent): C, 66.95; H, 7.96; N, 6.51. Found (percent): C, 67.22; H, 7.96; N, 6.65.

EXAMPLE 19 1,2,3,4-tetrahydro-3-hydroxy-6,7-dimethoxy-e-methyl-2- (p-tolylsulfonyl)-1-isoquinolineoctanoic acid 3-lactone A solution of 10 g. (0.029 m.) of 5,6,9,10,1l,12,13,14, 15,15a decahydro 14 hydroxy 2,3 dimethoxy- 13 methyl 9H azecino[2,1-a]isoquinolin 8 one in 250 ml. of pyridine is treated dropwise (45 min.) with a solution of 11.4 g. (0.06 m.) of p-toluenesulfonyl chloride in ml. of pyridine, and is stirred at room temperature for 22 hours. The reaction mixture is concentrated under reduced pressure at temperatures not exceeding 40. The residue is dissolved in 250 ml. of chloroform, washed consecutively with dilute HCl, 5% sodium hydroxide solution and H 0. Drying and evaporation of the chloroform solution yields 13.2 g. of 1,2,3,4-tetrahydro 3 hydroxy 6,7 dimethoxy (e) methyl- 2 (p tolylsulfonyl) 1 isoquinolineoctanoic acid 3-lactone. Crystallization from 100 ml. isopropanol affords 3 g. (21%) of 5,6,9,10,11,12,13,14,15,15a decahydro 14 hydroxy 2,3 dimethoxy 13 -methyl 8H- azecino[2,1-a]isoquinoline-S-one p-toluenesulfonate.

A second crop of crystalline material from the isopropanol mother liquor gives on recrystallization from ethyl acetate, 0.88 g. (6%) of lactone; M.P. 189190; Rf 0.8; k 1720 cm. (s.); 6 p.p.m. d. 0.93 (CH CH), 2.27 (CH C H 3.73, 3.84 (CH O), two proton multiplet in 4.3-4.8 area (equatorial H-3, 3H), q. 5.15 (H-l, Jab 12 cps., Jab 3.5 cps.), 6.28, 6.57 (dimethoxybenzene aromatic protons); 6.98, 7.12, 7.48, 7.63 (toluene aromatic protons).

Analysis.Ca1cd. for C H NO S (percent): C, 64.65; H, 7.03; S, 6.30. Found (percent): C, 64.88; H, 7.05; S, 6.28.

EXAMPLE 20 C11 0 09 g; C31 0 1H taining chloroform. The mixture is allowed to stand overnight and the solvent is removed in vacuo at room temperature. Chloroform is added and the evaporation is repeated. The glossy residue is treated with 200 ml. of ethyl acetate. The crystalline precipitate is filtered off and the filtrate is extracted with three 70 ml. portions of water.

The aqueous extracts are combined, made basic with saturated sodium bicarbonate solution, and extracted with chloroform. The chloroform extracts are dried and evaporated and the residue is recrystallized from ethyl acetate to yield 2.68 g. (39%) of ethyl 1,2,3,4tetrahydro-3-hydroxy 6,7 dimethoxy e methyl 1 isoquinoline octanoate; M.P. 82-83; x 1520 (v.s.), 1610 (ms), 1730 (v.s.), 3100 (m.), 3300 (m,), cmf A m (:2) shoulder 223 (3100), 282 (3800), 286 (3800); 6 p.p.m., d. 0.88 (CH CH), t, 1.22 (CH -CH2), 3.83 (CH O), q. .4.12 (CH -CH t. 4.39 (isoquinoline H1); 6.56 6.60 (aromatic H).

Analysis.-Calcd. for C H NO (percent): C, 67.14;

H, 8.97; N, 3.56. Found (percent): C, 67.42; H, 9.02; N, 3.63.

It is understood that the foregoing detailed description is given merely by way of illustration and that many variations may be made therein Without departing from the spirit of our invention.

Having described our invention, what we desire to secure by Letters Patent is:

1. A compound of the formula:

wherein B is oxygen or H2; A is CHOH, CHOSO2C6H4CH3 C=O, CH C=NOH, C=NOCOCH CONH; R and R are hydrogen, lower alkoxy, or hydroxy; R is .hydrogen, lower alkyl, or lower alkoxy; R is lower alkyl;

and n is 1 to 8, and the pharmaceutically acceptable acid addition salts thereof.

2.The compound of claim 1 which is: 5,6,10,1l,12,13, 15,15a-octahydro-2,3-dimethoxy-l3-methyl 9H azecino [2,1-a]isoquinoline-8,14-dione.

3. The compound of claim 1 which is: 5,6,10,11,l2,13, 15,15a octahydro 3 methoxy-13-methyl-9H-azecino [2,1-a]isoquinolin-8,14-dione.

4. The compound of claim 1 which is: 5,6,10,11,12,13, 15,15a octahydro 13 methyl 9H azecino [2,1-a] isoquinolin-8,14-dione 5. The compound of claim 1 which is: 5,6,9,10,11,12,13, 14,15,15a decahydro 2,3,15 ,trimethoxy 13 methyl- 9H-azecino[2,1-a]isoquinolin-8,14-dione.

6. The compound of claim 1 which is: 5,6,9,10,11,12,

13,15,15a octahydro 2,3 dimethoxy 13 methyl 9H- azecino [2, l-a] isoquinoline-8,14-dione, 14-oxime.

8. The compound of claim 1 which is: 5,6,9,10,l1,l2, 13,14,15, 15a decahydro 14 hydroxy 2,3 dimethoxy- 13-methyl-9H-azecino [2,1-a] isoquinolin-8-one.

9. The compound of claim 1 which is: 5,6,9,10,11,12, 13,14,15,15a decahydro 2,3 dimethoxy 13 methyl- SH-azecino[2,1-a]isoquinolin-14-ols.

10. The compound of claim 1 which is: 5,6,9,10,11, 12,l3,14,15,15a decahydro 2,3 dimethoxy 13 methyl-8H-azecino [2, 1-a]isoquinoline perchlorate.

11. The compound of claim 1 which is: 5,6,9,10,11,12, 13,14,15,l5a decahydro 2,3 dimethoxy 13 methyl- 8H-azecino [2,1-a] isoquinoline-14-one oxime.

12. The compound of claim 1 which is: 5,6,9,10,11, 12,13,14,-15,l5a decahydro 14 hydroxy 2,3 dimethoxy 13 methyl 8H azecino[2,1-a]isoquinoline- 8-one p-toluenesulfonate.

13. The compound of claim 1 which is: 5,6,9,l0,11,12, 13,14,15,15a decahydro 14 hydroxy 2,3 dimethoxy- 13-methyl-8H-azecino[2,1-a]isoquinoline-8-one benzoate.

14. The compound of claim 1 which is: 5,6,83,10,11, 12,13,14j,15a decahydro 2,3 dimethoxy 131'- methyl- 14H-azecin0[2,1-a]isoquinolin-14-one O-acetyl oxime.

15. A; process for the production of a compound of the formula: v

wherein R and R are hydrogen, lower alkoxy or hydroxy; R is hydrogen, lower alkyl or lower alkoxy; R is lower alkyl and n is 1 to 8; which comprises contacting a compound of the Formula I with a compound of the Formula II:

(CHEM R3CH2 at thetemperature from about -100" C. in a lower molecular weight alcohol or water.

References Cited UNITED STATES PATENTS 3,426,027 2/ 1969 Muller 260-289 DONALD G. DAUS, Primary Examiner U.S. Cl. X.R. 

